Elsevier

Neuroscience

Volume 153, Issue 3, 15 May 2008, Pages 733-750
Neuroscience

Neuroanatomy
Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: Autonomic pathway implicated in Parkinson's disease?

https://doi.org/10.1016/j.neuroscience.2008.02.074Get rights and content

Abstract

The protein alpha-synuclein is implicated in the development of Parkinson's disease. The molecule forms Lewy body aggregates that are hallmarks of the disease, has been associated with the spread of neuropathology from the peripheral to the CNS, and appears to be involved with the autonomic disorders responsible for the gastrointestinal (GI) symptoms of individuals afflicted with Parkinson's. To characterize the normative expression of alpha-synuclein in the innervation of the GI tract, we examined both the postganglionic neurons and the preganglionic projections by which the disease is postulated to retrogradely invade the CNS. Specifically, in Fischer 344 and Spragueā€“Dawley rats, immunohistochemistry in conjunction with injections of the tracer Dextranā€“Texas Red was used to determine, respectively, the expression of alpha-synuclein in the myenteric plexus and in the vagal terminals. Alpha-synuclein is expressed in a subpopulation of myenteric neurons, with the proportion of positive somata increasing from the stomach (āˆ¼3%) through duodenum (proximal, āˆ¼6%; distal, āˆ¼13%) to jejunum (āˆ¼22%). Alpha-synuclein is co-expressed with the nitrergic enzyme nitric oxide synthase (NOS) or the cholinergic markers calbindin and calretinin in regionally specific patterns: āˆ¼90% of forestomach neurons positive for alpha-synuclein express NOS, whereas āˆ¼92% of corpus-antrum neurons positive for alpha-synuclein express cholinergic markers. Vagal afferent endings in the myenteric plexus and the GI smooth muscle do not express alpha-synuclein, whereas, virtually all vagal preganglionic projections to the gut express alpha-synuclein, both in axons and in terminal varicosities in apposition with myenteric neurons. Vagotomy eliminates most, but not all, alpha-synuclein-positive neurites in the plexus. Some vagal preganglionic efferents expressing alpha-synuclein form varicose terminal rings around myenteric plexus neurons that are also positive for the protein, thus providing a candidate alpha-synuclein-expressing pathway for the retrograde transport of putative Parkinson's pathogens or toxins from the ENS to the CNS.

Section snippets

Subjects

Three- to 10-month-old, virgin male Fischer 344 (F344; n=42) and Spragueā€“Dawley (SD; n=12) rats were purchased from Harlan (Indianapolis, IN, USA). Rats were housed individually and maintained on a 12-h light/dark schedule at 22ā€“24 Ā°C. Solid chow (laboratory diet No. 5001; PMI Feeds, Inc., Brentwood, MO, USA) and tap water were available ad libitum. All procedures were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH

Pattern of innervation by axons expressing alpha-synuclein

Throughout the stomach and proximal duodenum, axons immunoreactive for alpha-synuclein were so densely distributed that the myenteric plexus was clearly delineated (Fig. 1). Large numbers of labeled fibers filled the interganglionic connectives, including the secondary and tertiary interganglionic connectives of the primary plexus. Individual axons were identifiable within the densely stained plexus, and were typically smooth in appearance when running within the connectives. Upon entering the

Discussion

In view of the conspicuous, though incompletely understood, roles of alpha-synuclein in synucleinopathies, including notably Parkinson's disease (e.g. Trojanowski and Lee 2002, Marti et al 2003, Norris et al 2004), the present experiment was designed to examine the pattern of expression of the protein in the autonomic circuitry of the proximal gut. The results delineate an extensive and complex network of vagal preganglionic axons and myenteric postganglionic neurons positive for

Conclusion

In summary, then, virtually all vagal motor fibers innervating the myenteric plexus of the proximal GI tract express alpha-synuclein in their axons and terminals. The preganglionic endings encircle and form appositions with myenteric postganglionic neurons, including those that express alpha-synuclein. The pathway of alpha-synuclein-positive vagal preganglionics that form appositions on postganglionic neurons that also express the protein satisfies the Braak proposal of a direct

Acknowledgments

We thank Michelle Murphy for her help with the SlideBook software, and Nazim Anwar for his expert assistance with the preparation of the medullas for FluoroGold analysis. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIH DK61317 and DK27627).

References (50)

  • R.J. Phillips et al.

    Tension and stretch receptors in gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology

    Brain Res Brain Res Rev

    (2000)
  • R.J. Phillips et al.

    Innervation of the gastrointestinal tract: patterns of aging

    Auton Neurosci

    (2007)
  • T.L. Powley et al.

    A fluorescent labeling strategy for staining the enteric nervous system

    J Neurosci Methods

    (1991)
  • C. Singaram et al.

    Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation

    Lancet

    (1995)
  • J.Q. Trojanowski et al.

    Parkinson's disease and related synucleinopathies are a new class of nervous system amyloidoses

    Neurotoxicology

    (2002)
  • S. Yu et al.

    Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody

    Neuroscience

    (2007)
  • R.D. Abbott et al.

    Bowel movement frequency in late-life and incidental Lewy bodies

    Mov Disord

    (2007)
  • R.D. Abbott et al.

    Midlife adiposity and the future risk of Parkinson's disease

    Neurology

    (2002)
  • A. Adamczyk et al.

    Expression of alpha-synuclein in different brain parts of adult and aged rats

    J Physiol Pharmacol

    (2005)
  • G. Andringa et al.

    Mapping of rat brain using the synuclein-1 monoclonal antibody reveals somatodendritic expression of alpha-synuclein in populations of neurons homologous to those vulnerable to Lewy body formation in human synucleopathies

    J Neuropathol Exp Neurol

    (2003)
  • H.R. Berthoud et al.

    Topography of efferent vagal innervation of the rat gastrointestinal tract

    Am J Physiol

    (1991)
  • A. Bloch et al.

    Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects

    Neuropathol Appl Neurobiol

    (2006)
  • H. Braak et al.

    Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen

    J Neural Transm

    (2003)
  • H. Braak et al.

    Parkinson's disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons

    Acta Neuropathol (Berl)

    (2007)
  • M.S. Brenz Verca et al.

    Distribution of alpha- and gamma-synucleins in the adult rat brain and their modification by high-dose cocaine treatment

    Eur J Neurosci

    (2003)
  • Cited by (162)

    • The link between the gut microbiota and Parkinson's Disease: A systematic mechanism review with focus on Ī±-synuclein transport

      2021, Brain Research
      Citation Excerpt :

      These results together with the findings of Perez-Prado et al. (2018a) are very salient to the mechanism as a whole, demonstrating the role of microbiota in impaired barrier function and inflammation (Perez-Pardo et al., 2018a), as well as microglia activation and Ī±-synuclein pathology (Sampson et al., 2016). Eight animal studies, including two transgenic models of PD (Noorian et al., 2012; Parrella et al., 2019), identified a possible pathway for the transsynaptic retrograde transport of Ī±-synuclein from the ENS to the CNS (Table 2.3 (Ahn et al., 2020; Challis et al., 2020; Holmqvist et al., 2014; Kim et al., 2017, 2019; Phillips et al., 2008)). The study design and findings of Holmqvist et al. (2014) are particularly pertinent to the investigation of Ī±-synuclein transport from the gut to brain, indicating that Ī±-synuclein forms are transported via the vagal nerve to the DMV.

    View all citing articles on Scopus
    View full text